We are interested in how synapses form in the brain. The objective of this proposal is to investigate the mechanism underlying the novel finding that Brain-Specific Angiogenesis Inhibitor 2 (BAI2) increases synapse number when overexpressed in cultured neurons. BAI2 is a member of adhesion G-protein coupled receptor (GPCR) family, comprised of a large N- terminal extracellular (adhesive) domain followed by a seven transmembrane GPCR domain. This novel finding extends our published work that identified a functional mutation in a critical extracellular region of BAI2 underlying a forward mutagenesis hyperactivity screen in mice that reduced surface expression of BAI2 in heterologous cells. Our hypothesis is that the intracellular C-terminus of BAI2 is indispensable for the increase in synapse number that we observed. Specifically, there are two motifs?a domain that binds a key regulator of the actin cytoskeleton and a PDZ binding sequence?that may be critical mediators of early synapse formation. We will employ a molecular biology approach coupled with super-resolution microscopy in dissociated hippocampal neurons in the presence or absence of BAI2 to test this hypothesis. Intriguingly, a de novo C-terminal mutation of BAI2 that leads to constitutive receptor signaling was identified in a human patient suffering from progressive spastic paraparesis and other symptoms. Thus, results of these studies will provide insight into BAI2 function in synapse development as well as dysfunction that leads to human disease.
Deficits in synapse development and function underlie many neurological and psychiatric diseases including epilepsy and schizophrenia. Proteins that regulate synapse development and function represent promising targets for drug developments. This potential remains largely unrealized despite a wealth of tantalizing preclinical data. This project will investigate mechanisms of trans-synaptic adhesion complexes in excitatory synapse development in the hippocampus, an important brain region underlying cognitive function.
